PROJECT SUMMARY/ABSTRACT The recent rise in the use of electronic nicotine delivery systems (ENDS), or e-cigarettes, is fueling interest in the relative contribution of nicotine versus constituent tobacco compounds in the abuse liability of tobacco products. Originally designed to be used as smoking cessation aids, these nicotine vaporizers are being marketed as safe alternatives to tobacco with a dizzying array of available flavors and levels of nicotine content. Because of the wide misconception that use of ENDS is not harmful because tobacco is not burned, there is a gradually-emerging population who are initiating their nicotine addiction by ?vaping? these ENDS rather than through actual tobacco products. This population is therefore pre-exposed to nicotine, and may be at subsequent greater risk for tobacco dependence. Indeed, there is early evidence that those individuals who begin consuming nicotine in ENDS form have a greater chance of transitioning to tobacco consumption than their never-using peers. The interactions between nicotine and constituent tobacco compounds have not yet been addressed in the context of this enhanced risk of tobacco abuse following nicotine pre-exposure. The objective of this research is to fill that scientific gap by assessing the impact of the addition of constituent compounds to nicotine in an intravenous self-administration model in male and female adult and adolescent rats. In Aim 1, nornicotine and anatabine will be added to self-administered nicotine in adults; in Aim 2, nornicotine and anatabine will be added to self-administered nicotine in adolescents. In both Aims, we will assess the impact of the added constituent compound on the motivational value of nicotine. The effect of adding a constituent compound in each Aim is expected to reduce simple self- administration because their agonist actions at nicotinic acetylcholine receptors provides a level of nicotine substitution. However, nornicotine, but not anatabine, has also been shown to have reinforcing properties, likely due to its far greater relative affinity for ?4?2* receptors. Therefore, nornicotine, but not anatabine, is expected to enhance the motivational value of nicotine as measured by repeated sessions on a progressive ratio schedule because of this additive reinforcement value. A differential impact of the addition of constituent compounds to nicotine will provide a unique perspective on the tenacity of tobacco dependence. Indeed, current investigations of the impact of tobacco constituent compounds on nicotine abuse liability revolve around regulatory research focused on the effects of reducing nicotine content in tobacco. The current study, however, will investigate the relative contribution of nicotine versus constituent tobacco compounds on the abuse liability of tobacco products from the perspective of this emerging population who begin their nicotine use with ENDS rather than tobacco. This conceptually innovative approach incorporating pharmacological manipulations with motivational assessments using repeated progressive ratio schedules will allow us to begin to address a problem that is only likely to grow with time.